Pipofezine

Pipofezine, sold under the brand name Azafen or Azaphen, is an antidepressant approved in Russia for the treatment of depression.[1][2][3][4] It was introduced in the late 1960s and is still used today.[5][6]

Pipofezine
Clinical data
Trade namesAzafen, Azaphen
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
IUPAC name
  • 5-methyl-3-(4-methylpiperazin-1-yl)pyridazino[3,4-b][1,4]benzoxazine
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC16H19N5O
Molar mass297.362 g·mol−1

Pipofezine has been shown to act as a potent inhibitor of the reuptake of serotonin.[7][8] In addition to its antidepressant action, pipofezine has sedative effects as well, suggesting antihistamine activity.[4] Other properties such as anticholinergic or antiadrenergic actions are less clear but are likely.

Synthesis
Patent:[9] Precursor:[10][11]

2-Benzoxazolinone [59-49-4] (1) is treated with dimethylsulfate in aqueous KOH solution to give 3-Methyl-2-Benzoxazolinone [21892-80-8] (2). This is further reacted with 3,4,6-Trichloropyridazine [6082-66-2] (3) catalyzed by KOH in ethanol solvent to give 2-Chloro-10-methyl-3,4-diazaphenoxazine [27225-84-9] (4)

Ex 7: Alkylation with Methylpiperazine (5) in cyclohexanol, with azeotropic removal of the solvent gives pipofezine (3).

References
  1. Aleeva GN, Molodavkin GM, Voronina TA (July 2009). "Comparison of antidepressant effects of azafan, tianeptine, and paroxetine". Bulletin of Experimental Biology and Medicine. 148 (1): 54–6. doi:10.1007/s10517-009-0638-4. PMID 19902096. S2CID 23923093.
  2. Swiss Pharmaceutical Society (2000). Index Nominum 2000: International Drug Directory (Book with CD-ROM). Boca Raton: Medpharm Scientific Publishers. ISBN 3-88763-075-0.
  3. European Drug Index, 4th Edition. Boca Raton: CRC Press. 1998. ISBN 3-7692-2114-1.
  4. John E. Macor (2009). Annual Reports in Medicinal Chemistry, Volume V44. Boston: Academic Press. ISBN 978-0-12-374766-2.
  5. Mashkovskii MD; Polezhaeva AI; Avrutskii GIa; Vertozgadova OP; Smulevich AB (1969). "[The pharmacologic properties and therapeutic effectiveness of the new antidepressant preparation Azaphen]". Zhurnal Nevropatologii i Psikhiatrii Imeni S.S. Korsakova (in Russian). 69 (8): 1234–8. PMID 5392529.
  6. Shinaev NN, Akzhigitov RG (2005). "[Azaphen: a return to clinical practice]". Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova (in Russian). 105 (10): 55–6. PMID 16281382.
  7. Avdulov NA, Maĭsov NI (November 1981). "[Atypical antidepressants: effect on synaptosomal uptake of serotonin and GABA]". Biulleten' Eksperimental'noĭ Biologii i Meditsiny (in Russian). 92 (11): 564–6. PMID 7198493.
  8. Valdman AV, Avdulov NA, Rozganets VV, Rusacov DY (1983). "Behavioural and neurochemical studies of the action of atypical antidepressants". Acta Physiologica et Pharmacologica Bulgarica. 9 (3): 3–10. PMID 6142583.
  9. Anon, FR 1576534 (1969-08-01).
  10. Gortinskaya, T. V., Nyrkova, V. G., Savitskaya, N. V., Shchukina, M. N. (June 1971). "Synthesis of substituted 5H-pyradazino [3,4-b]-1,4-benzoxazine (3,4-diazaphenoxazine): III. Synthesis of 2-chloro-10-alkyl- and 2-chloro-10-dialkylaminoalkyl-3,4-diazaphenoxazines". Chemistry of Heterocyclic Compounds. 7 (6): 698–702. doi:10.1007/BF00476810. eISSN 1573-8353. ISSN 0009-3122.
  11. Tatyana Vladimirovna Gortinskaya, et al. U.S. Patent 3,961,058 (1976 to Moscow, USSR).


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